A renal disorder is any alteration in normal physiology and function of the kidney. Renal disorders can result from a wide range of acute and chronic conditions and events, including physical, chemical, or biological injury, insult, or trauma, disease, such as, for example, hypertension, diabetes, congestive heart failure, lupus, sickle cell anemia, and various inflammatory and autoimmune diseases, HIV-associated nephropathies, etc. Renal disorders can lead to reduced kidney function, hypertension, and renal failure, seriously compromising quality of life, sometimes requiring dialysis and in certain circumstances, kidney transplantation.
Diabetic nephropathy is a major long-term complication of diabetes mellitus, and is the leading indication for dialysis and kidney transplantation in the United States. (Marks and Raskin, 1998, Med Clin North Am, 82:877-907.) The development of diabetic nephropathy is seen in 25 to 50% of Type I and Type 2 diabetic individuals. Accordingly, diabetic nephropathy is the most common cause of end-stage renal disease and kidney failure in the Western world.
Contributing risk factors associated with the development of diabetic nephropathy (and other renal disorders) in subjects with Type 1 or Type 2 diabetes include hyperglycemia, hypertension, altered glomerular hemodynamics, and increased or aberrant expression of various growth factors, including transforming growth factor-beta (TGFβ), insulin-like growth factor (IGF)-I, vascular endothelial growth factor-a (VEGF-A), and connective tissue growth factor (CTGF). (See, e.g., Flyvbjerg (2000) Diabetologia 43:1205-23; Brosius (2003) Exp Diab Res 4:225-233; Gilbert et al.
Current treatment strategies directed at slowing the progression of diabetic nephropathy using various approaches, including optimized glycemic control (through modification of diet and/or insulin therapy) and hypertension control, have demonstrated varying degrees of success. For example, both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), administered to reduce hypertension, have been shown to delay progression or development of nephropathy and macroalbuminuria. Several clinical trials have established the benefits of ACE inhibitors and ARBs in patients with diabetes. However, although ACE inhibitors have been shown to delay renal decline in patients with Type 1 diabetes, the renoprotective effect of these agents in patients with Type 2 diabetes is less clear. (Raij (2003) Am J Hypertens 16:46 S-49S.)
Further, while glycemic and blood pressure control therapies significantly decrease the morbidity and mortality associated with diabetic nephropathy by delaying progression of associated pathologies, such conventional therapies do not adequately halt the progression of the disease and thus fail to provide a complete therapeutic effect. In addition, administration of ACE inhibitors or ARBs, the current standard of care, are not universally effective and only minimally delay, but do not remove, the need for kidney transplantation.
Other treatment strategies have focused on one or more growth factors as therapeutic targets. Therapies directed at inhibiting VEGF or TGFβ, either alone or in combination with ACE inhibitors or ARBs, have been examined. (See, e.g., De Vriese et al. (2001) J Am Soc Nephrol 12:993-1000; Flyvbjerg et al. (2002) Diabetes 51:3090-3094; Ziyadeh et al, (2000) Proc Natl Acad Sci 97:8015-8020; Chen et al. (2003) Biochem Biophys Res Commun 300:16-22; and Benigni et al. (2003) J Am Soc Nephrol 14:1816-1824.) Such therapeutic approaches, however, have not provided amelioration of all aspects of renal pathology (e.g., altered and impaired renal function and structure) associated with diabetic nephropathy. For example, inhibition of TGFβ as a therapeutic target for diabetic nephropathy was not effective at attenuating albuminuria in db/db mice, despite the beneficial effects such treatment had on glomerular matrix expansion. (See Ziyadeh et al, supra) In addition, while administration of anti-VEGF antibodies to diabetic db/db mice provided benefit to diabetes-associated increased permeability in the kidney, only minimal beneficial effects on mesangial expansion were observed. (See Flyvbjerg et al (2002), supra.) Therefore, although such therapies offer promise, alone or in combination, none has resulted in amelioration of both early (e.g., glomerular hyperfiltration, increased glomerular filtration rate. Microalbuminuria, etc.) and late (e.g., decreased glomerular filtration rate, macroalbuminuria, excessive mesangial matrix expansion, etc.) pathological features associated with chronic renal disease, e.g., diabetic nephropathy. Thus, there is a need in the art for a complete therapy for treatment of diabetic nephropathy that ameliorates both early and late stages symptoms and pathologies associated with the development and progression of the disease.
In addition to the above deficiencies, current therapies for diabetic nephropathy have limited applicability/efficacy due to lack of specificity. In particular, VEGF- or TGFβ-targeted therapies may compromise the beneficial activities of these growth factors, such as angiogenesis, tumor suppression, and proper immune system development. For example, while TGFβ has been associated with development of fibrosis, it is also an important mediator of immune development and tumor suppression, suggesting that inhibition of TGFβ might have unwanted and potentially adverse secondary effects. Therefore, there is a need in the art for a more selective therapeutic approach for diabetic nephropathy.
In summary, there is an existing need in the art for a therapeutic approach for treating renal disease, in particular diabetic nephropathy, which is effective at various stages (e.g., early stage and late stage diabetic nephropathy) in the development and progression of the disease. In particular, there is a need for a complete treatment for diabetic nephropathy, one effective in treating both early stage features and late stage features of diabetic nephropathy such as, for example, hyperfiltration (early stage), increased glomerular permeability (early stage), increased glomerular filtration rate (early stage), microalbuminuria (early stage), macroalbuminuria (late stage), and decreased glomerular filtration rate (late stage). There is a need for a therapeutic approach that more completely addresses various and distinct processes associated with development and progression of diabetic nephropathy and other renal diseases. In particular, there is a need for therapies that target both non-fibrotic (e.g., hyperfiltration) and fibrotic (e.g., mesangial matrix expansion) processes associated with diabetic nephropathy. In addition, there is a need for a therapeutic approach for treating renal disease in general, and diabetic nephropathy in particular, that provides both structural and functional benefits.
The present invention addresses these needs by identifying the role of CTGF in various processes associated with the development and progression of renal disorders such as, e.g., diabetic nephropathy, and by providing methods for inhibiting and preventing these processes. The invention further addresses existing needs by providing methods and agents that can be applied to the treatment and prevention of renal diseases, particularly, renal disease associated with diabetes, and most particularly, diabetic nephropathy.